The present invention relates to bicyclic heterocycles of general formula 
the tautomers, the stereoisomers, and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, particularly an inhibitory effect on signal transduction mediated by tyrosine kinases, the use thereof for treating diseases, particularly tumoral diseases, diseases of the lungs and respiratory tract, and the preparation thereof.
In the above general formula I
Ra denotes a benzyl or 1-phenylethyl group or a phenyl group substituted by the groups R1 and R2, where
R1 denotes a hydrogen, fluorine, chlorine, or bromine atom, or a methyl, trifluoromethyl, cyano, or ethynyl group, and
R2 denotes a hydrogen or fluorine atom,
Rb denotes an R3Oxe2x80x94COxe2x80x94CH2xe2x80x94Nxe2x80x94CH2xe2x80x94CH2xe2x80x94OH group optionally substituted at the methylene groups by 1 or 2 methyl or ethyl groups, where
R3 represents a hydrogen atom or a C1-4-alkyl group,
a 2-oxomorpholin-4-yl group which may be substituted by 1 or 2 methyl or ethyl groups, or a N-[(1,3-dioxolan-2-yl)methyl]methylamino group,
Rc denotes a hydrogen atom, a methoxy, ethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy, or tetrahydropyranylmethoxy group, and
n denotes an integer from the range from 1 to 3 with the proviso that the following compounds:
4-[(3-bromophenyl)amino]-6-({4-[N-(1,3-dioxolan-2-ylmethyl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-methoxyquinazoline;
4-[(3-bromophenyl)amino]-6-{[4-(2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxyquinazoline;
4-[(3-bromophenyl)amino]-6-[(4-{N-[(tert-butyloxycarbonyl)methyl]-N-(2-hydroxyethyl)amino}-1-oxo-2-buten-1-yl)amino]-7-methoxyquinazoline;
4-[(3-bromophenyl)amino]-6-({4-[N-(carboxymethyl)-N-(2-hydroxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-methoxyquinazoline;
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline;
4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[(ethoxycarbonyl)methyl]-N-(2-hydroxyethyl)amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline;
4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[(ethoxycarbonyl)methyl]-N-(2-hydroxy-2-methylpropyl)amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline;
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(2,2-dimethyl-6-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline;
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5,5-dimethyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline;
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline;
(R)-4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[1-(ethoxycarbonyl)ethyl]-N-(2-hydroxyethyl)amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline; and
(R)-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(3-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
are excluded.
Preferred compounds of the above general formula I are those wherein
Ra denotes a benzyl or 1-phenylethyl group or a phenyl group substituted by the groups R1 and R2, where
R1 denotes a hydrogen, fluorine, chlorine, or bromine atom, a methyl, trifluoromethyl, cyano, or ethynyl group, and
R2 denotes a hydrogen or fluorine atom,
Rb denotes an R3Oxe2x80x94COxe2x80x94CH2xe2x80x94Nxe2x80x94CH2xe2x80x94CH2xe2x80x94OH group optionally substituted at the methylene groups by 1 or 2 methyl or ethyl groups, where
R3 represents a hydrogen atom or a C1-4-alkyl group,
a 2-oxomorpholin-4-yl group which may be substituted by 1 or 2 methyl or ethyl groups, or an N-[(1,3-dioxolan-2-yl)methyl]methylamino group,
Rc denotes a hydrogen atom, a methoxy, ethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy, or tetrahydropyranylmethoxy group, and
n denotes an integer from the range from 1 to 3 with the proviso that the following compounds:
4-[(3-bromophenyl)amino]-6-({4-[N-(1,3-dioxolan-2-ylmethyl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-methoxyquinazoline;
4-[(3-bromophenyl)amino]-6-{[4-(2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxyquinazoline;
4-[(3-bromophenyl)amino]-6-[(4-{N-[(tert-butyloxycarbonyl)methyl]-N-(2-hydroxyethyl)amino}-1-oxo-2-buten-1-yl)amino]-7-methoxyquinazoline;
4-[(3-bromophenyl)amino]-6-({4-[N-(carboxymethyl)-N-(2-hydroxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-methoxyquinazoline;
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline;
4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[(ethoxycarbonyl)methyl]-N-(2-hydroxyethyl)amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline;
4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[(ethoxycarbonyl)methyl]-N-(2-hydroxy-2-methylpropyl)amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline;
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(2,2-dimethyl-6-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline;
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5,5-dimethyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline;
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline;
(R)-4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[1-(ethoxycarbonyl)ethyl]-N-(2-hydroxyethyl)amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline;
(R)-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(3-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline;
4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-[N-(1,3-dioxolan-2-ylmethyl)-N-methylamino]-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline;
4-(3-chloro-4-fluorophenyl)amino]-6-{[4-(3-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline; and
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
are excluded, the tautomers, the stereoisomers, and the salts thereof.
Particularly preferred compounds of the above general formula I are those wherein
Ra denotes a benzyl or 1-phenylethyl group or a phenyl group substituted by the groups R1 and R2, where
R1 denotes a fluorine, chlorine, or bromine atom, or a methyl or ethynyl group, and R2 denotes a hydrogen or fluorine atom,
Rb denotes an R3Oxe2x80x94COxe2x80x94CH2xe2x80x94Nxe2x80x94CH2xe2x80x94CH2xe2x80x94OH group substituted at the methylene groups by 1 or 2 methyl or ethyl groups, where
R3 represents a C1-4-alkyl group,
a 2-oxomorpholin-4-yl group which is substituted by 1 or 2 methyl or ethyl groups,
Rc denotes a hydrogen atom, a methoxy, ethoxy, 2-methoxyethoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy, or tetrahydropyranylmethoxy group, and
n denotes the number 1 or 2 with the proviso that the following compounds
4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[(ethoxycarbonyl)methyl]-N-(2-hydroxy-2-methylpropyl)amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline;
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(2,2-dimethyl-6-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline;
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5,5-dimethyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline;
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline;
(R)-4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[1-(ethoxycarbonyl)ethyl]-N-(2-hydroxyethyl)amino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline;
(R)-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(3-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline;
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(3-methyl-2-oxomorpholin-4-yl)-1-oxo-2buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline; and
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline
are excluded, particularly those wherein
Ra denotes a benzyl or 1-phenylethyl group or a phenyl group substituted by the groups R1 and R2, where
R1 denotes a fluorine, chlorine, or bromine atom, and
R2 denotes a hydrogen or fluorine atom,
Rb denotes a 2-oxomorpholin-4-yl group which is substituted by 1 or 2 methyl or ethyl groups,
Rc denotes a hydrogen atom, or a methoxy, ethoxy, 2-methoxyethoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy, or tetrahydropyranylmethoxy group, and
n denotes the number 1, with the proviso that the following compounds
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(2,2-dimethyl-6-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline;
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5,5-dimethyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline;
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline;
(R)-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(3-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline;
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(3-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline; and
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
are excluded, the tautomers, the stereoisomers, and the salts thereof.
Most particularly preferred compounds of the above general formula I are those wherein
Ra denotes a 1-phenylethyl or a 3-chloro-4-fluorophenyl group,
Rb denotes a 2-oxomorpholin-4-yl group which is substituted by 1 or 2 methyl groups, or a 2-oxomorpholin-4-yl group which is substituted by an ethyl group,
Rc denotes a hydrogen atom, or a methoxy, 2-methoxyethoxy, cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy, or tetrahydropyranylmethoxy group, and
n denotes the number 1, with the proviso that the following compounds
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(2,2-dimethyl-6-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5,5-dimethyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
(R)-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(3-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(3-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline, and
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
are excluded, the tautomers, the stereoisomers, and the salts thereof.
The following compounds are mentioned by way of example as being particularly preferred compounds of general formula I:
4-[(3-chloro-4-fluorophenyl)amino]-6-[(4-{N-[(1,3-dioxolan-2-yl)methyl]-N-methylamino}-1-oxo-2-buten-1-yl)amino]-7-cyclopropylmethoxyquinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((S)-6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((S)-3-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5,5-dimethyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-(2-methoxyethoxy)quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((S)-6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5,5-dimethyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclobutyloxyquinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5,5-dimethyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline,
4-[(R)-(1-phenylethyl)amino]-6-{[4-(5,5-dimethyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5,5-dimethyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-3-yl)oxy]quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((S)-6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-3-yl)oxy]quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5,5-dimethyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydropyran-4-yl)oxy]quinazoline,
4-[(R)-(1-phenylethyl)amino]-6-{[4-(5,5-dimethyl-2-oxomorpholin-4-yl)-1-oxo-2buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(2,2-dimethyl-6-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydropyran-4-yl)oxy]quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5,5-dimethyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxyquinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5,5-dimethyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5,5-dimethyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(6-ethyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,
4-[(R)-(1-phenylethyl)amino]-6-{[4-((S)-6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxyquinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((S)-6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-3-yl)oxy]quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(5,5-dimethyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}quinazoline,
4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydropyran-4-yl)oxy]quinazoline, and
4-[(R)-(1-phenylethyl)amino]-6-{[4-((S)-6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}quinazoline,
the tautomers, the stereoisomers, and the salts thereof.
The compounds of general formula I may be prepared by the following methods, for example:
a) reacting a compound of general formula 
xe2x80x83wherein
Ra and Rc are as hereinbefore defined, with a compound of general formula
Z1xe2x80x94COxe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x94Rbxe2x80x83xe2x80x83(III)
wherein
Rb and n are as hereinbefore defined, and
Z1 represents a leaving group such as a halogen atom, e.g., a chlorine or bromine atom, or a hydroxy group.
The reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, acetonitrile, toluene, chlorobenzene, tetrahydrofuran, methylene chloride/tetrahydrofuran, or dioxane, optionally in the presence of an inorganic or organic base and optionally in the presence of a dehydrating agent, expediently at temperatures between xe2x88x9250xc2x0 C. and 150xc2x0 C., preferably at temperatures between xe2x88x9220xc2x0 C. and 80xc2x0 C.
With a compound of general formula III wherein Z1 denotes a leaving group, the reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, acetonitrile, toluene, chlorobenzene, tetrahydrofuran, methylene chloride/tetrahydrofuran, or dioxane conveniently in the presence of a tertiary organic base such as triethylamine, pyridine, or 2-dimethylaminopyridine, or N-ethyldiisopropylamine (Hxc3xcnig base), while these organic bases may simultaneously also act as solvent, or in the presence of an inorganic base such as sodium carbonate, potassium carbonate, or sodium hydroxide solution expediently at temperatures between xe2x88x9250xc2x0 C. and 150xc2x0 C., preferably at temperatures between xe2x88x9220xc2x0 C. and 80xc2x0 C.
With a compound of general formula III wherein Z1 denotes a hydroxy group, the reaction is preferably carried out in the presence of a dehydrating agent, e.g., in the presence of isobutyl chloroformate, thionyl chloride, trimethyl chlorosilane, phosphorus trichloride, phosphorus pentoxide, hexamethyldisilazane, N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/N-hydroxysuccinimide, or 1-hydroxybenzotriazole, and optionally also in the presence of 4-dimethylaminopyridine, N,Nxe2x80x2-carbonyldiimidazole, or triphenylphosphine/carbon tetrachloride, expediently in a solvent such as methylene chloride, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylsulfoxide, ethylene glycol diethylether, or sulfolane, and optionally in the presence of a reaction accelerator such as 4-dimethylaminopyridine at temperatures between xe2x88x9250xc2x0 C. and 150xc2x0 C., but preferably at temperatures between xe2x88x9220xc2x0 C. and 80xc2x0 C.
b) reacting a compound of general formula 
xe2x80x83optionally formed in the reaction mixture,
wherein
Ra, Rc, and n are as hereinbefore defined, and
Z2 denotes a leaving group such as a halogen atom or a substituted sulfonyloxy group such as a chlorine or bromine atom, a methanesulfonyloxy or p-toluenesulfonyloxy group, or a hydroxy group, with a compound of general formula
Hxe2x80x94Rbxe2x80x83xe2x80x83(V)
wherein
Rb is as hereinbefore defined.
The reaction is expediently carried out in a solvent such as isopropanol, acetonitrile, butanol, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide, dimethylsulfoxide, methylene chloride, ethylene glycol monomethyl ether, ethylene glycol diethyl ether, or sulfolane, or in a mixture of solvents, optionally in the presence of an inorganic base, e.g., sodium carbonate or potassium hydroxide, or a tertiary organic base, e.g., triethylamine or N-ethyldiisopropylamine (Hxc3xcnig base), while these organic bases may simultaneously also serve as solvent, and optionally in the presence of a reaction accelerator such as an alkali metal halide at temperatures between xe2x88x9220xc2x0 C. and 150xc2x0 C., but preferably at temperatures between xe2x88x9210xc2x0 C. and 100xc2x0 C. The reaction may, however, also be carried out without a solvent or in an excess of the compound of general formula V used.
If Z2 in a compound of general formula IV denotes a hydroxy group, the reaction is preferably carried out in the presence of an activating agent, e.g., in the presence of thionyl chloride or phosphorus trichloride, conveniently in a solvent such as acetonitrile, methylene chloride, tetrahydrofuran, dioxane, toluene, chlorobenzene, or ethylene glycol diethyl ether and optionally in the presence of a reaction accelerator such as sodium iodide at temperatures between xe2x88x9250xc2x0 C. and 150xc2x0 C., but preferably at temperatures between xe2x88x9220xc2x0 C. and 80xc2x0 C.
The compound of formula IV may also be prepared in a one-pot process from the compound of formula II and a corresponding carboxylic acid derivative and further reacted directly.
c) cyclizing a compound of general formula 
xe2x80x83optionally formed in the reaction mixture
wherein
Ra, Rc, and n are as hereinbefore defined, and
Rbxe2x80x2 denotes an optionally substituted N-(carboxymethyl)-N-(2-hydroxyethyl)amino or N-(C1-4-alkyloxycarbonylmethyl)-N-(2-hydroxyethyl)amino group which can be converted by cyclization into an optionally substituted 2-oxomorpholin-4-yl group.
The reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, acetonitrile, dimethylformamide, dimethylsulfoxide, sulfolane, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran, or dioxane, expediently in the presence of an anhydrous acid such as trifluoroacetic acid, methanesulfonic acid, or sulfuric acid or in the presence of a dehydrating agent, e.g., in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/N-hydroxysuccinimide, or 1-hydroxybenzotriazole, N,Nxe2x80x2-carbonyldiimidazole, or triphenylphosphine/carbon tetrachloride, at temperatures between xe2x88x9220xc2x0 C. and 200xc2x0 C., but preferably at temperatures between xe2x88x9210xc2x0 C. and 160xc2x0 C.
If according to the invention a compound of general formula I is obtained which contains an optionally substituted 2-oxomorpholin-4-yl group, this may be converted by hydrolysis into a corresponding compound which contains an optionally substituted N-(carboxymethyl)-N-(2-hydroxyethyl)amino group.
The optional subsequent hydrolysis is carried out, for example, by hydrolysis in an aqueous solvent, e.g., in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water, or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, or sulfuric acid or in the presence of an alkali metal base such as sodium hydroxide, at temperatures between 0xc2x0 C. and 120xc2x0 C., preferably at temperatures between 10xc2x0 C. and 100xc2x0 C.
In the reactions described hereinbefore, any reactive groups present such as hydroxy, carboxy, phosphono, or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
For example, a protecting group for a hydroxy group may be a trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, trityl, benzyl, or tetrahydropyranyl group,
protecting groups for a carboxy group may be a trimethylsilyl, methyl, ethyl, tert-butyl, benzyl, or tetrahydropyranyl group, and
protecting groups for an imino group may be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl, or 2,4-dimethoxybenzyl group.
Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g., in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water, or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid, or sulfuric acid, or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g., in the presence of iodotrimethylsilane, at temperatures between 0xc2x0 C. and 120xc2x0 C., preferably at temperatures between 10xc2x0 C. and 100xc2x0 C.
However, a benzyl, methoxybenzyl, or benzyloxycarbonyl group is cleaved, for example hydrogenolytically, e.g., with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate, or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0xc2x0 C. and 100xc2x0 C., but preferably at ambient temperatures between 20xc2x0 C. and 60xc2x0 C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisole.
A tert-butyl or tert-butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol, or diethyl ether.
A trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50xc2x0 C. and 120xc2x0 C. or by treating with sodium hydroxide solution, optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0xc2x0 C. and 50xc2x0 C.
Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.
Thus, for example, the cis/trans mixtures may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. N. L. Allinger and E. L. Eliel in xe2x80x9cTopics in Stereochemistryxe2x80x9d, Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g., by chromatography and/or fractional crystallization, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
The enantiomers are preferably separated by column separation on chiral phases or by recrystallization from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as, e.g., esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g., on the basis of their differences in solubility, while the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are, e.g., the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid, or quinic acid. An optically active alcohol may be for example (+) or (xe2x88x92)-menthol and an optically active acyl group in amides, for example, may be a (+)- or (xe2x88x92)-menthyloxycarbonyl.
Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, or maleic acid.
The compounds of general formulae II to VI used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature (cf. Examples I to VIII).
As already mentioned hereinbefore, the compounds of general formula I according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an inhibiting effect on signal transduction mediated by the Epidermal Growth Factor receptor (EGF-R), while this may be achieved for example by inhibiting ligand bonding, receptor dimerization, or tyrosine kinase itself. It is also possible that the transmission of signals to components located further down is blocked.
The biological properties of the new compounds were investigated as follows:
The inhibition of the EGF-R-mediated signal transmission can be demonstrated, e.g., with cells which express human EGF-R and whose survival and proliferation depend on stimulation by EGF or TGF-alpha. A cell line of murine origin dependent on interleukin-3-(IL-3) which was genetically modified to express functional human EGF-R was used here. The proliferation of these cells known as F/L-HERc can therefore be stimulated either by murine IL-3 or by EGF (cf. T. von Rxc3xcden et al. in EMBO J. 7, 2749-2756 (1988) and J. H. Pierce et al. in Science 239, 628-631 (1988)).
The starting material used for the F/L-HERc cells was the cell line FDC-P1, the production of which has been described by T. M. Dexter et al. in J. Exp. Med. 152, 1036-1047 (1980). Alternatively, however, other growth-factor-dependent cells may also be used (cf., for example, J. H. Pierce et al. in Science 239, 628-631 (1988), H. Shibuya et al. in Cell 70, 57-67 (1992) and W. S. Alexander et al. in EMBO J. 10, 3683-3691 (1991)). For expressing the human EGF-R cDNA (cf. A. Ullrich et al. in Nature 309, 418-425 (1984)) recombinant retroviruses were used as described by T. von Rxc3xcden et al., EMBO J. 7, 2749-2756 (1988), except that the retroviral vector LXSN (cf. A. D. Miller et al. in BioTechniques 7, 980-990 (1989)) was used for the expression of the EGF-R cDNA and the line GP+E86 (cf. D. Markowitz et al. in J. Virol. 62, 1120-1124 (1988)) was used as the packaging cell.
The test was performed as follows:
F/L-HERc cells were cultivated in RPMI/1640 medium (Bio Whittaker), supplemented with 10% fetal calf serum (FCS, Boehringer Mannheim), 2 mM glutamine (Bio Whittaker), standard antibiotics and 20 ng/ml of human EGF (Promega), at 37xc2x0 C. and 5% CO2. In order to investigate the inhibitory activity of the compounds according to the invention, 1.5xc3x97104 cells per well were cultivated in triplicate in 96-well dishes in the above medium (200 xcexcl), the cell proliferation being stimulated with either EGF (20 ng/ml) or murine IL-3. The IL-3 used was obtained from culture supernatants of the cell line X63/0 mIL-3 (cf. H. Karasuyama et al. in Eur. J. Immunol. 18, 97-104 (1988)). The compounds according to the invention were dissolved in 100% dimethylsulfoxide (DMSO) and added to the cultures in various dilutions, the maximum DMSO concentration being 1%. The cultures were incubated for 48 hours at 37xc2x0 C.
In order to determine the inhibitory activity of the compounds according to the invention the relative cell number was measured in O.D. units using the Cell Titer 96(trademark) Aqueous Non-Radioactive Cell Proliferation Assay (Promega). The relative cell number was calculated as a percentage of the control (F/LHERc cells without inhibitor) and the concentration of active substance which inhibits the proliferation of the cells by 50% (IC50) was derived therefrom. The following results were obtained:
The compounds of general formula I according to the invention thus inhibit signal transduction by tyrosine kinases, as demonstrated by the example of the human EGF receptor, and are therefore useful for treating pathophysiological processes caused by hyperfunction of tyrosine kinases. These are, e.g., benign or malignant tumors, particularly tumors of epithelial and neuroepithelial origin, metastasization, and the abnormal proliferation of vascular endothelial cells (neoangiogenesis).
The compounds according to the invention are also useful for preventing and treating diseases of the airways and lungs which are accompanied by increased or altered production of mucus caused by stimulation by tyrosine kinases, e.g., in inflammatory diseases of the airways such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasis, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, xcex11-antitrypsin deficiency, or coughs, pulmonary emphysema, pulmonary fibrosis, and hyperreactive airways.
The compounds are also suitable for treating diseases of the gastrointestinal tract and bile duct and gall bladder which are associated with disrupted activity of the tyrosine kinases, such as may be found, e.g., in chronic inflammatory changes such as cholecystitis, Crohn""s disease, ulcerative colitis, and ulcers in the gastrointestinal tract or such as may occur in diseases of the gastrointestinal tract which are associated with increased secretions, such as Mxc3xa9nxc3xa9trier""s disease, secreting adenomas, and protein loss syndrome, and also for treating nasal polyps and polyps of the gastrointestinal tract of various origins such as villous or adenomatous polyps of the large intestine, but also polyps in familial polyposis coli, in intestinal polyps in Gardner""s syndrome, in polyps throughout the entire gastrointestinal tract in Peutz-Jeghers Syndrome, in inflammatory pseudopolyps, in juvenile polyps, in colitis cystica profunda and in pneumatosis cystoides intestinales.
In addition, the compounds of general formula I and the physiologically acceptable salts thereof may be used to treat kidney diseases, particularly in cystic changes as in cystic kidneys, for treating renal cysts which may be idiopathic in origin or occur in syndromes such as tubercular sclerosis, in von Hippel-Lindau syndrome, in nephrophthisis, and spongy kidney and other diseases caused by abnormal function of tyrosine kinases, such as, e.g., epidermal hyperproliferation (psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation of hematopoietic cells, etc.
By reason of their biological properties the compounds according to the invention may be used on their own or in conjunction with other pharmacologically active compounds, for example in tumour therapy, in monotherapy or in conjunction with other anti-tumour therapeutic agents, for example in combination with topoisomerase inhibitors (e.g., etoposide), mitosis inhibitors (e.g., vinblastine), compounds which interact with nucleic acids (e.g., cis-platin, cyclophosphamide, adriamycin), hormone antagonists (e.g., tamoxifen), inhibitors of metabolic processes (e.g., 5-FU etc.), cytokines (e.g., interferons), antibodies, etc. For treating respiratory tract diseases, these compounds may be used on their own or in conjunction with other therapeutic agents for the airways, such as substances with a secretolytic, broncholytic, and/or anti-inflammatory activity. For treating diseases in the region of the gastrointestinal tract, these compounds may also be administered on their own or in conjunction with substances having an effect on motility or secretion, or anti-inflammatory substances. These combinations may be administered either simultaneously or sequentially.
These compounds may be administered either on their own or in conjunction with other active substances by intravenous, subcutaneous, intramuscular, intraperitoneal, or intranasal route, by inhalation or transdermally or orally, while aerosol formulations are particularly suitable for inhalation.
For pharmaceutical use the compounds according to the invention are generally used for warm-blooded vertebrates, particularly humans, in doses of 0.01-100 mg/kg of body weight, preferably 0.1-15 mg/kg. For administration they are formulated with one or more conventional inert carriers and/or diluents, e.g., with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose, or fatty substances such as hard fat or suitable mixtures thereof in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, sprays, or suppositories.
The following Examples are intended to illustrate the present invention without restricting it:
Preparation of the starting compounds: